Transcript Document

US EPA Regulation of Endocrine
Disrupting Chemicals
2015 Regulatory Conference ECPA-ECCA
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WILLIAM JORDAN
DEPUTY DIRECTOR, OFFICE OF PESTICIDE PROGRAMS
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Overview
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US and international developments on endocrine disruptors policy: do
opportunities for cooperation exist?
 Pesticide Regulation in the US
 US EPA’s Current Endocrine Disruptor Screening Program (EDSP)
 Future Directions for the EDSP
 Concluding Thoughts
Pesticide Regulation in the US
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What is a Pesticide?
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 In the US, a pesticide is defined as any substance
or mixture of substances intended for preventing,
destroying, repelling, or mitigating any pest.
Examples:
insecticides
rodenticides
fungicides
plant growth regulators
herbicides
antimicrobials
microbials
biochemicals
U. S. Pesticide Laws
Federal Food Drug
And Cosmetic Act
(FFDCA)
*MRLs (Tolerance) Established
*Maximum Residue Level
Reasonable Certainty of No Harm
(Risk only)
Federal Insecticide Fungicide
And Rodenticide Act
(FIFRA)
Products Registered
Periodic Reevaluation
No Unreasonable Adverse Effects
(Risk/Benefit)
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Human Health Risk Assessment for Pesticides (1)
EPA follows the National Academy of Sciences (NAS)
four-step risk assessment paradigm*:
*From the National Research Council’s Risk Assessment in the
Federal Government: Managing the Process, 1983.
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Human Health Risk Assessment for Pesticides (2)
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 “Hazard” is a type of adverse effect; Hazard identification – what are the
possible toxic effects
 “Dose–response” refers the relationship between a dose of a pesticide and the
occurrence of an adverse effect; at what dose(s) are the possible effects seen?
 “Exposure” is the level of contact of a pesticidal substance
 “Risk” refers to the likelihood of an adverse effect; risk takes account of
hazard, dose-response, and exposure
Data Requirements to Support Pesticide Registration &
MRLs
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Typically EPA requires over 100 studies for a new pesticide:
 Human Hazard Studies: multiple endpoints (all organ systems and
functions); durations (acute – chronic); lifestages (fetus – adult); routes
(oral, dermal, inhalation)
 Ecological Toxicity Studies: multiple species (birds, fish, insects,
invertebrates, plants)
 Human Exposure Studies: occupational (handlers, workers);
bystanders; residential activities
 Environmental Exposure Studies: hydrolysis, photodegradation,
solubility, leaching, volatility, aerobic and anaerobic metabolism
Risks to Humans Assessed for Multiple Pathways and
Routes of Exposure
 Oral exposure
Food supply
 Drinking water
 Incidental ingestion
 Dermal exposure
 Applying pesticide
 Harvesting crops
 Spray drift
 Turf contact
 Inhalation exposure
 Applying pesticide
 Bystander

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US EPA’s Current Endocrine
Disruptor Screening Program
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1996 Legislative Mandates
1996 Federal Food, Drug and Cosmetic Act, section 408(p)
Requires the U. S. EPA to develop a screening program using appropriate
validated test systems and other scientifically relevant methods to determine
whether pesticide chemicals may have an effect in humans that is similar to an
effect produced by a naturally occurring estrogen, or other such endocrine
effect as the Administrator may designate.
1996 Safe Drinking Water Act Amendments, section 1457
Testing of chemical substances that may be found in sources of drinking
water, if substantial human populations may be exposed.
Slide 11 of X
EDSP Chronology
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1996 FFDCA and SDWA
1998 EDSTAC recommendations
1999 EPA established the EDSP
2008 Validated eleven Tier 1 screening assays
2009 Initial test orders for Tier 1 assays
2011 EDSP21 Work plan
2012 EDSP Comprehensive Mgmt Plan
1999-2014 Scientific Advisory Panel Reviews
Public Engagement for EDSP
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EDSP established and implemented with robust public engagement:
 The Endocrine Disruptor Screening and Testing Advisory
Committee (EDSTAC) of 1996-1998
 Endocrine Disruptor Methods Validation Advisory Committee
(2004)
 Public comments on policy papers and management plans
 Public reports to Congress and Pesticide Program Dialogue
Committee
 EPA’s FIFRA Scientific Advisory Panel
 EPA website: http://www.epa.gov/scipoly/oscpendo/index.htm
1998 Endocrine Disruptor Screening and Testing Advisory
Committee (EDSTAC)
EDSTAC Key Recommendations:
 Expand Protection to Include Human Health and
Wildlife
 Include Estrogen, Androgen and Thyroid Pathways
 Prioritization based on exposure and high throughput
screening [HTS] for bioactivity
 Develop a Two-Tiered Screening and Testing
Program: bioactivity and adversity
Slide 14 of X
EDSTAC Tiered Testing Approach
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EDSTAC recommended a two-tiered approach
 Tier 1 battery (in vitro and in vivo assays)
To identify substances that have the potential to interact with the
estrogen, androgen, or thyroid hormone systems
 Tier 2 testing (multigenerational tests)
To identify, and establish a dose-response relationship for any adverse
effects that might result from the interactions identified through the
Tier 1 assays
EDSP Prioritization, Screening & Testing
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Prioritization
Exposure
Screening
Bioactivity
Testing
DoseResponse/Adversity
Relies on:
Relies on:
Relies on:
• Monitoring
data
• OSRI
• EDSP Tier 1 data
• OSRI
• EDSP Tier 2
data
• OSRI
UNEP Advisory Group Meeting
December 12, 2014
Slide 16 of 24
Tier 1 Screening Assays: Bioactivity
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Tier 2 Test Methods: Adversity
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 Rat: Two-generation rat reproduction test (OECD TG 416)
Rat: Extended F1-Generation (OECD TG 443)
 Fish: Medaka Multi-generation Toxicity Test (MMT) and
Medaka Reproduction Test (MRT) methods
 Frog: characterize perturbations of normal development
and growth – Xenopus Laevis
 Bird: determine long-term effects of maternal transfer
and in ovo exposure – Japanese Quail
•
M
F
EDSP Tier 1 Data Review: Current Pace
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20092010
EDSP Issued
Initial Tier 1
Test Orders on
67 chemicals
2014-2015
Agency
Completes 52
Tier 1 Data
Reviews and
WOE
Determinations
2012-2013
Tier 1 Data
Submitted to the
Agency on 52
chemicals
Future Direction for U.S. Endocrine
Disruptor Screening Program
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EDSP Universe of Chemicals
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Chemical List
Number of Compounds
Conventional Active Ingredients
838
Antimicrobial Active Ingredients
324
Biological Pesticide Active Ingredients
287
Non Food Use Inert Ingredients
2,211
Food Use Inert Ingredients
1,536
Fragrances used as Inert Ingredients
1,529
Safe Drinking Water Act Chemicals
3,616
TOTAL
10,341
Evolution of EDSP
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 Based on current pace it could take
decades to screen all 10,000 chemicals
in EDSP Universe
 Use compuational toxicology to
rapidly screen chemicals for potential
bioactivity and exposure
 Implement a strategic approach to
prioritize chemicals for targeted
screening
EDSP List 2
107 Chemicals
EDSP Chemical
Universe
10,000
chemicals
(FIFRA &
SDWA)
EDSP List 1
67 Chemicals
Use of HTS / Computational Toxicology
Methodologies: Objectives
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1.
2.
3.
Prioritize chemicals for further EDSP
screening and testing based on
estimated bioactivity
Contribute to the weight of evidence
evaluation of a chemical’s potential
bioactivity
Substitute for specific endpoints in the
EDSP Tier 1 battery
UNEP Advisory Group Meeting
December 12, 2014
Slide 23 of 24
ToxCast High Throughput Screening (HTS)
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 Detect agonist and antagonist
activities
18 Estrogen receptor assays
9 Androgen receptor assays
3 Thyroid receptor assays
http://www.epa.gov/ncct/toxcast/
Example: Estrogen Agonism
ID
Assay Name
Source
A1
NVS bovine ER
Novascreen
A2
NVS human ER
Novascreen
A3
NVS mouse ERa
Novascreen
A4
OT ERa-ERa (8 h)
Odyssey Thera
A5
OT ERa-ERa (24 h)
Odyssey Thera
A6
OT ERa-ERb (8 h)
Odyssey Thera
A7
OT ERa-ERb (24 h)
Odyssey Thera
A8
OT ERb-ERb (8 h)
Odyssey Thera
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A9
OT ERb-ERb (24 h) Odyssey Thera
OT GFP ERa-ERE (2
A10 h)
Odyssey Thera
OT GFP ERa-ERE (8
A11 h)
Odyssey Thera
A12 ATG ERa (TRANS)
Attagene
Gene
ESR1
Species
Bos taurus
Homo
ESR1
sapiens
Mus
Esr1
musculus
Homo
ESR1
sapiens
Homo
ESR1
sapiens
ESR1,
Homo
ESR2
sapiens
ESR1,
Homo
ESR2
sapiens
Homo
ESR2
sapiens
Homo
ESR2
sapiens
Homo
ESR1, ERE sapiens
Homo
ESR1, ERE sapiens
Homo
ESR1
sapiens
Homo
Type
Receptor
Binding
Receptor
Binding
Receptor
Binding
Dimerization
Dimerization
Dimerization
Dimerization
Dimerization
Dimerization
DNA Binding
DNA Binding
RNA Reporter
Gene
RNA Reporter
Proposed Methodological Approach
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 Use computational tools to model ER
bioactivity
 16 ToxCast assays relevant to agonist pathway

Model AUC for R1 (agonist) and R2 (antagonist)
activities
UNEP Advisory Group Meeting
December 12, 2014
Slide 26 of 24
Scientific Confidence Needed To Use any New Assay
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Are reference chemicals that include a range of structures
and potencies accurately detected?
 Step
1: Does CompTox accurately identify chemicals
with demonstrated in vitro bioactivities?
 Step
2: Does CompTox accurately identify chemicals
with demonstrated in vivo bioactivities?
Step 1: In Vitro Estrogen-Active Chemicals
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40 reference chemicals selected
for recognized in vitro ER activity
and include:
• Range of structures
• Range of potencies
•
•
•
•
Strong: AC50 < 0.0001 μM
Moderate: AC50 < 0.1 μM
Weak: AC50 < 1 μM
Very Weak: all other actives
• Peer Reviewed
• OECD
• ICCVAM
http://ntp.niehs.nih.gov/pubhealth/evalatm/i
ccvam/test-method-evaluations/endocrinedisruptors/in-vitro-assayreview/brd/index.html
Step 1: ToxCast results vs. reference
chemical results
Reference
Chemicals
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ToxCast
POS
NEG
POS
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0
NEG
2
10
Overall concordance ~90% (36/40)
Step 2: In vivo Estrogen-Active Chemicals
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Comparison of ToxCast results for chemicals with
recognized in vivo ER activity
 Leverage existing in vivo data
Systematic literature search of publically available (e.g.
PubMed) Uterotrophic studies
Review published studies for QC and consistency with EPA
(890.1600) guideline
 6 minimum criteria to establish methodological consistency
 Two independent reviewers evaluate studies based on criteria
 All 6 criteria must be met to consider a study “guideline-like”


Step 2: ToxCast results vs. Uterotrophic
results
Uterotrophic
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ToxCast
POS
NEG
POS
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8
NEG
6
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Overall concordance ~84% (75/89)
Integrated Bioactivity-Exposure Ranking: Objective
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Prioritize chemicals for further
EDSP screening and testing
based on rank of ER bioactivity
and estimated exposure
UNEP Advisory Group Meeting
December 12, 2014
Slide 32 of 24
Proposed Method
Bioactivity
ToxCast
HTTK
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Exposure
ExpoCast
Integrated
Bioactivity
Exposure
Ranking
(IBER)
Prioritization
Some or All
EDSP Tier 1
Assays
Screening
Testing
UNEP Advisory Group Meeting
December 12, 2014
Some or All
EDSP Tier 2
Assays
Slide 33 of 24
Integrated Bioactivity-Exposure Ranking
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FIFRA Scientific Advisory Panel Peer Reviews
http://www.epa.gov/scipoly/sap/index.htm

Prioritizing the Universe of Endocrine Disruptor Screening Program (EDSP) Chemicals Using
Computational Toxicology Tools (January 2013)


http://www.regulations.gov (Search under EPA docket number: EPA-HQ-OPP-2013-0230)
New High Throughput Methods To Estimate Chemical Exposure (July 2014)


http://www.regulations.gov (Search under EPA docket number:EPA-HQ-OPP-2013-0182)
Weight-of-Evidence: Evaluating Results of EDSP Tier 1 Screening (July 2013)


http://www.regulations.gov (Search under EPA docket number:EPA-HQ-OPP-2013-0075)
Endocrine Disruptor Screening Program (EDSP) Tier 2 Ecotoxicity Tests (June 2013)


http://www.regulations.gov (Search under EPA docket number: EPA-HQ-OPP-2012-0818)
Endocrine Disruptor Screening Program (EDSP) Tier 1 Screening Assays and Battery
Performance (May 2013)


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http://www.regulations.gov (Search under EPA docket number: EPA-HQ-OPP-2014-0331)
Endocrine Activity and Exposure-based Prioritization and Screening (December 2014)

http://www.regulations.gov (Search under EPA docket ID: EPA-HQ-OPP-2014-0614)
EDSP Prioritization, Screening & Testing
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Prioritization
Screening
Bioactivity/Exposure
Bioactivity
Relies on:
Relies on:
• QSARs
• ToxCast/ExpoC
ast
• Monitoring
data
• OSRI
•
•
•
•
UNEP Advisory Group Meeting
QSARs
ToxCast
EDSP Tier 1 data
OSRI
December 12, 2014
Testing
DoseResponse/Adversity
Relies on:
• EDSP Tier 2
data
• OSRI
Slide 36 of 24
Concluding Thoughts
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US Views on EC Roadmap for EDs
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 The United States expressed concerns that the options provided in the
EC’s Roadmap for defining criteria for identifying endocrine disruptors,
specifically as it relates to plant protection products, does not appear to
take into account risk from exposure in its approach, and may impose
unnecessary and burdensome restrictions, that do not benefit public
health or environmental protection.
 Further, implementation of an EU policy that removes the requirement
for conducting a full risk assessment, [as required by the WTO], is likely
to have severe implications for EU imports of U.S. agricultural goods
and plant protection products which serve an important public health
objective by controlling pests and diseases.
Are There Opportunities for
EU-US Collaboration for ED
Chemicals?
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YES!